Method for treating uterine fibroids

ABSTRACT

The invention relates to a method for treating uterine fibroids, which method comprises administering to a patient in need thereof, an effective amount of 17α-acetoxy-11β-[4-N,N-dimethylamino-phenyl)-19-norpregna-4,9-diene-3,20-dione (ulipristal) or any metabolite thereof. More particularly, the method is useful for reducing or stopping bleeding in a patient afflicted with uterine fibroids, and/or for reducing the size of uterine fibroids.

This application is a continuation of U.S. application Ser. No.13/622,892, filed Sep. 19, 2012, which is a continuation of U.S.application Ser. No. 12/021,610, filed Jan. 29, 2008 (now U.S. Pat. No.8,299,050), the entire contents of which are incorporated herein byreference.

This invention relates to a method for treating uterine fibroids, alsocalled leiomyomata, or tumors deriving therefrom.

Leiomyomata are common pelvic fibroid tumors occurring in up to 20% ofwomen over 30 years of age. Leiomyomata represent one of the mostfrequent indications of surgical procedures in woman of reproductiveage. Studies show that up to 77% of women have microscopic ormacroscopic uterine fibroids at the time of menopause (Cramer et al,1990). Leiomyomata may be 1 mm to 20 cm in diameter.

Leiomyomata are monoclonal sex-hormone responsive tumors of myometrialcells with abundant extra cellular collagen matrix. The histologicalappearance is similar to that of normal myometrium surrounded by apseudocapsule of compressed myometrium, although areas of fibrosis andcalcification (thought to represent degeneration) may be present.Leiomyomata are almost always benign in pre-menopausal women but may beindistinguishable from leiomyosarcomas, a tumor most common inpost-menopausal women.

While these tumors may be asymptomatic, they frequently have clinicalmanifestations, such as excessive uterine bleeding, chronic pelvic painor pressure, or dysmenorrhea, especially when large. Miscarriage andinfertility are associated with fibroids as well (Somigliana et al,2007). However, it is the location, rather than the size of the fibroidthat appears related to these last two clinical problems. The treatmentof leiomyomata depends on the symptoms, location, and size of the tumor,and the age of the woman. Expectant treatment is recommended forasymptomatic women and medical treatment of menorrhagia for those withexcessive bleeding. Because high levels of estradiol cause tumourgrowth, other approaches include temporizing until menopause, whengonadal steroid levels fall. In other studies, induction of a <<medicalmenopause>> with low estradiol and progesterone levels by GnRH agonistsled to rapid shrinkage of the tumors. However, medical therapy with GnRHagonists causes hot flushes and osteoporosis (the latter when given formore than six months), so they are recommended for use only up to sixmonths. The selective progesterone receptor modulator mifepristone alsoreduced fibroid size in a dose-dependent manner (Murphy 1995, Zeng1998).

Because there are no safe and effective long-term medical therapies forleiomyomata, surgical extirpation by hysterectomy or myomectomy remainsthe major therapeutic option for symptomatic women and accounted for300,000 hysterectomies and 20,000 myomectomies in 1997 in the UnitedStates (Farquhar 2002). In the United States, the annual inpatient costfor these procedures was more than two billion dollars in 1997 (AHRQreport 2001). Thus, the impact of this condition on the public healthand health care cost is significant.

The American College of Obstetricians and Gynecologists (ACOG) hasdefined conditions under which hysterectomy is an appropriate therapy ofleiomyoma for women who do not wish to maintain fertility (ACOG PracticeBulletin 1994). These include excessive bleeding, pelvic discomfort orincreased urinary frequency or uterine enlargement greater than 12 weeksgestation size that is a concern to the patient. Laparoscopic orhysteroscopic myomectomies may be an alternative to laparotomy orhysterectomy depending on the skill of the laproscopist and whether thefibroids are submucosal and can be accessed by the hysteroscope (ACOGPractice Bulletin 2000). Endometrial ablation to destroy the endometriumtargets the source of endometrial bleeding and may be effective whenthat is the primary symptom. A number of small studies with limitedfollow-up suggest that uterine artery embolization can decreasebloodflow to the uterus, and reduce leiomyoma and uterine size. However,the procedure may be painful and cause infection and bleeding that leadsto surgery. Because of damage to the uterine and ovarian blood supply,it is not recommended for pre-menopausal women interested in preservingfertility. Pregnancy outcomes following this procedure are not wellstudied.

Clinicians would welcome new medical treatments to reduce fibroidsymptoms, e.g. either before menopause or before surgery.

SUMMARY OF THE INVENTION

The invention provides a method for treating uterine fibroids or tumorsderiving therefrom, which method comprises administering to a patient inneed thereof, an effective amount of ulipristal or of a metabolitethereof.

In a preferred embodiment, the patient is administered with a tabletcomprising ulipristal or a metabolite thereof.

Surprisingly enough, the inventors have shown that a low dosage, e.g. adaily dosage of 5 to 15 mg, preferably 10 mg, ulipristal was the mosteffective.

It is thus proposed to administer ulipristal or a metabolite thereof ata daily dosage of 5 to 15 mg, preferably 10 mg.

The patient may be administered with an oral dosage of ulipristal or ofa metabolite thereof during a period of about 2 to about 4 months, whichperiod can be repeated once a year.

Ulipristal or a metabolite thereof is particularly efficient to reduceor stop bleeding in a patient afflicted with uterine fibroids, or toreduce the size of uterine fibroids.

Ulipristal or a metabolite thereof may be useful as a contraceptivewhile treating the uterine fibroids or tumors derived thereof.

In a particular embodiment, the patient is affected with metastaticleiomyoma, also called metastatic or metastasizing leiomyomatosis.

A subject of the invention is a method for treating metastasizingleiomyomatosis, which method comprising administering to a patient inneed thereof, an effective amount of17α-acetoxy-11β-[4-N,N-dimethylamino-phenyl)-19-norpregna-4,9-diene-3,20-dione(ulipristal) or of a metabolite thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph that shows the treatment-related change in fibroidvolume after 3 months administration with ulipristal (CDB-2914).PLC=placebo; T1=10 mg CDB-2914; T2=20 mg CDB-2914; p=0.01 for T1 or T2vs. PLC.

FIG. 2 is a graph that shows the average number of bleeding days bycycle and treatment group, i.e. placebo, 10 mg, or 20 mg ulipristal(CDB-2914) orally.

DETAILED DESCRIPTION OF THE INVENTION

Ulipristal, formerly known as CDB-2914, is17α-acetoxy-11β-[4-N,N-dimethylamino-phenyl)-19-norpregna-4,9-diene-3,20-dione,represented by formula I:

It is a well-known steroid, more specifically a 19-norprogesterone,which possesses antiprogestational and antiglucocorticoidal activity.This compound, and methods for its preparation, are described in U.S.Pat. Nos. 4,954,490, 5,073,548, and 5,929,262, and international patentapplications WO2004/065405 and WO2004/078709. Properties of thiscompound are further described in Blithe et al, 2003.

Metabolites of CDB-2914, include those described in Attardi et al, 2004,e.g. monodemethylated CDB-2914 (CDB-3877); didemethylated CDB-2914(CDB-3963); 17alpha-hydroxy CDB-2914 (CDB-3236); aromatic A-ringderivative of CDB-2914 (CDB-4183).

It is now proposed to use ulipristal or a metabolite thereof fortreating uterine fibroids, more particularly for reducing or stoppingbleeding in a patient afflicted with uterine fibroids, reducing the sizeof uterine fibroids and/or reducing uterine volume

More particularly the inventors have shown in a randomized,placebo-controlled, double blinded, parallel trial, that ulipristalsignificantly reduces fibroid volume after 3 months, and stops bleeding.

Ulipristal or a metabolite thereof alleviates symptoms of uterinefibroids, including bleeding, pelvic pain, pressure.

Ulipristal or a metabolite thereof is useful for preventing or treatinganemia in patients afflicted with uterine fibroids.

It is also useful for preventing or treating leiomyosarcomas and forpreventing dissemination of uterine fibroids to other organs.

The inventors further have shown that ulipristal or a metabolite thereofis efficient against pelvic and lung lesions in metastasizingleiomyomatosis after three months.

More generally, the invention relates to a method for treating tumorsthat derive from leiomyomata, including benign or cancerous tumors, e.g.leiomyosarcomas, leiomyomatosis or metastasizing leiomyomatosis.Metastasizing leiomyomatosis originates from an antecedent leiomyoma ofthe uterus in virtually all cases. It appears that tumor metastasizes tolungs or other extrauterine tissues via hematogenous spread. However,the origin of the tumor remains controversial.

Drug Delivery:

Ulipristal or a metabolite thereof may be administered by any convenientroute, including oral, buccal, parenteral, transdermal, vaginal,uterine, rectal, etc.

For a brief review of present methods for drug delivery, see, Langer,Science 249:1527-1533 (1990), which is incorporated herein by reference.Methods for preparing administrable compounds are known or are apparentto those skilled in the art and are described in more detail in, forexample, Remington's Pharmaceutical Science, 17th ed., Mack PublishingCompany, Easton, Pa. (1985), which is incorporated herein by reference,and which is hereinafter referred to as “Remington.”

For solid compositions, conventional nontoxic solid carriers may be usedwhich include, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharine, talcum, cellulose,glucose, sucrose, magnesium, carbonate, and the like. For oraladministration, a pharmaceutically acceptable nontoxic composition isformed by incorporating any of the normally employed excipients, such asthose carriers previously listed.

Oral solid dosage forms preferentially are compressed tablets orcapsules. Compressed tablets may contain any of the excipients describedabove which are diluents to increase the bulk of the ulipristal so thatproduction of a compressed tablet of practical size is possible.Binders, which are agents which impart cohesive qualities to powderedmaterials are also necessary. Starch, gelatin, sugars such as lactose ordextrose, and natural and synthetic gums are used. Disintegrants arenecessary in the tablets to facilitate break-up of the tablet.Disintegrants include starches, clays, celluloses, algins, gums andcrosslinked polymers. Lastly small amounts of materials known aslubricants and glidants are included in the tablets to prevent adhesionto the tablet material to surfaces in the manufacturing process and toimprove the flow characteristics of the powder material duringmanufacture. Colloidal silicon dioxide is most commonly used as aglidant and compounds such as talc or stearic acids are most commonlyused as lubricants. Procedures for the production and manufacture ofcompressed tablets are well known by those skilled in the art (SeeRemington).

Capsules are solid dosage forms using preferentially either a hard orsoft gelatin shell as a container for the mixture of ulipristal or ametabolite thereof and inert ingredients. Procedures for production andmanufacture of hard gelatin and soft elastic capsules are well known inthe art (See Remington).

Buccal forms or devices are also useful, such as those described in U.S.patent application 20050208129, herein incorporated by reference. U.S.patent application 20050208129 describes a prolonged release bioadhesivemucosal therapeutic system containing at least one active principle,with an active principle dissolution test of more than 70% over 8 hoursand to a method for its preparation. Said bioadhesive therapeutic systemcomprises quantities of natural proteins representing at least 50% byweight of active principle and at least 20% by weight of said tablet,between 10% and 20% of a hydrophilic polymer, and compressionexcipients, and comprising between 4% and 10% of an alkali metalalkylsulphate to reinforce the local availability of active principleand between 0.1% and 1% of a monohydrate sugar.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compounds and a sterile vehicle, water being preferred.Ulipristal or a metabolite thereof, depending on the vehicle andconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the compound can be dissolved in water forinjection and filtered sterilized before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanesthetic, preservative and buffering agents can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. The drylyophilized powder is then sealed in the vial and an accompanying vialof water for injection is supplied to reconstitute the liquid prior touse. Parenteral suspensions can be prepared in substantially the samemanner except that the compounds are suspended in the vehicle instead ofbeing dissolved and sterilization cannot be accomplished by filtration.The compound can be sterilized by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of ulipristal.

Additionally, a suppository can be employed to deliver ulipristal. Theactive compound can be incorporated into any of the known suppositorybases by methods known in the art. Examples of such bases include cocoabutter, polyethylene glycols (carbowaxes), polyethylene sorbitanmonostearate, and mixtures of these with other compatible materials tomodify the melting point or dissolution rate. These suppositories canweigh from about 1 to 2.5 gm.

Transdermal delivery systems comprising a penetration enhancer and anocclusive backing are of use to deliver ulipristal or a metabolitethereof. Examples of penetration enhancers include dimethyl sulfoxide,dimethyl acetamide and dimethylformamide.

Systems comprising polymeric devices which slowly release or slowlyerode and release within the body to provide continuous supplies ofulipristal are also of use. Suitable delivery systems includesubcutaneous devices or implants such as those routinely used to delivernorgestrienone or progestin R2323 and other medicaments.

In calculating the dosage for individuals one has to take intoconsideration the weight of the individual and the mode ofadministration. The following guidelines provide levels of ulipristalwhich are clinically effective.

Presuming an average weight of 120 pounds or 53 kilograms, the dailyunit dosage of ulipristal is preferably between 5 to 15 mg per day.Surprisingly enough, the reduction of fibroid volume is more importantwith an oral dose of 10 mg, compared to 20 mg. An oral dose of 10 mg perday is thus most preferred. A lower dosage is also contemplated, e.g.between 1 mg and 10 mg daily, preferably between 5 and 10 mg daily. Theoral route is preferred. Other routes of administration can be suitablein comparison with oral routes using blood levels to provide clinicalsuccess.

Preferably the amount of ulipristal or a metabolite thereof is effectiveto alleviate the symptoms of uterine leiomyomata without clinicallysignificant antiglucocorticoid activity.

In a particular embodiment, the patient may be administered with an oraldosage of ulipristal during a period of about 2 to about 4 months.

In a preferred embodiment, the invention provides a method for treatingleiomyomata or tumors deriving therefrom in women comprising theadministration of a daily dosage of between 5 and 15 mg ulipristal or ametabolite thereof administered orally, in a micronized form.

Once the leiomyomata tumors have fully responded, a maintenance dosageof around 5 mg can be administered over a long period, e.g., in excessof 12 months.

The method according to the invention then further comprises a period oftreatment during which a daily dosage of ulipristal or a metabolitethereof is administered, wherein said dosage is administered at lessthan one half the initial treatment daily dosage.

In a particular embodiment, the treatment period may be repeated once ayear, or every two years.

The Patient:

The patient can be any human female, but may also be a non-humanmammalian female. The patient may be administered with ulipristal or ametabolite thereof at any time when needed.

However it may be of particular interest to administer ulipristal or ametabolite thereof before undergoing surgery of the uterus or non- orminimally invasive removal or destruction of the fibroids.

Indeed the treatment with ulipristal or a metabolite thereof stops allbleeding and renders the patient amenorrheic, which improves hemostasisand general condition of the patient before surgery. Furthermore itfavors non- or minimally invasive removal or destruction of thefibroids, against invasive surgery like myomectomy, hysterectomy.Surgical interventions and uterine artery embolisation can then beperformed by means of a laparoscope or transvaginally preferably.Ultrasound or thermal treatment may also be sufficient to destroy theremaining fibroids. ExAblate® device may be useful in that respect. Thisdevice provides a uterine-sparing alternative for women that is anon-invasive treatment. It combines two systems—a magnetic resonanceimaging (MRI) machine to visualize patient anatomy, map the volume offibroid tissue to be treated, and monitor the temperature of the uterinetissue after heating, and a focused ultrasound beam that heats anddestroys the fibroid tissue using high frequency, high-energy soundwaves.

The following examples are provided by way of illustration only and notby way of limitation. Those of skill will readily recognize a variety ofnoncritical parameters which could be changed or modified to yieldessentially similar results.

EXAMPLES Example 1 Randomized, Placebo-Controlled, Double Blinded,Parallel Trial of the Selective Progesterone Receptor Modulator,Ulipristal (CDB-2914)

Materials and Methods:

Healthy women aged 33-50 years with symptomatic fibroids and regularmenstrual cycles were considered for enrollment.

Inclusion criteria included regular cycles and contraceptive use, andsymptomatic fibroids as defined by ACOG practice bulletin 1994:

-   -   Excessive uterine bleeding evidenced by either of the following:        profuse bleeding with flooding or clots or repetitive periods        lasting for more than 8 days; or anemia due to acute or chronic        blood loss;    -   or pelvic discomfort caused by leiomyomata, either acute or        severe or chronic lower abdominal or low back pressure or        bladder pressure with urinary frequency not due to urinary tract        infection.

Exclusion criteria included pregnancy, hemoglobin <10 g/dL, currenthormone therapy, rapidly enlarging uterus and FSH >20 IU/mL. MR imageswere obtained to record fibroid number, location and volume, beforestarting study drug and within 2 weeks of surgery. Women took ulipristalat an oral dose of 10 or 20 mg, or placebo (PLC: microcrystallinecellulose) for 3 cycles, or 90 days if they became anovulatory. Thepercent change in total fibroid volume was compared. Wilcoxon rank sumtest and t-test were used as needed.

Results:

22 women met inclusion criteria and 18 women (72% Black, 28% White)completed the study. The six who received PL had similar mean age andBMI to ulipristal group. Complete data on overall change in fibroidvolume as determined by MR imaging were available from the 18completers. During the three month study interval, the total fibroidvolume increased by 6% among those receiving PLC; those receiving 10 mgand 20 mg demonstrated a 36% and 21% reduction in fibroid volume,respectively (see FIG. 1). When the two CDB-2914 groups were combined incomparison to PLC, there was a significant reduction in total fibroidvolume after three months of therapy (PLC: 6%; CDB-2914: −29%; p=0.01).

Additional analyses evaluated treatment-related differences in menstrualfunction. Women receiving PLC had monthly menses throughout the studyinterval. On the contrary, there was only a single episode of menstrualbleeding occurring in a subject receiving 10 mg; no woman receiving 20mg had any bleeding (see FIG. 2). When compared to PLC, CDB-2914 wasassociated with a significant reduction in menses with evidence of adose-dependent effect (p<0.001).

One patient had complex endometrial hyperplasia without atypia atsurgery.

Conclusions:

Compared to Placebo, ulipristal at 10 or 20 mg daily significantlyreduced the size of fibroids by 36% and 21%, respectively, after 90days, and induced amenorrhea.

Example 2 Gene Expression Profiling Study

Materials and Methods:

Pre-menopausal women with symptomatic fibroids received ulipristal (10or 20 mg; n=12) or placebo (PL) (n=6) in a blinded, randomizedallocation, for 90 days before hysterectomy. No other hormonal therapywas given. Fibroid tissue and adjacent myometrium were collected atsurgery and processed in RNAlater (for RNA isolation). Fibroid tissuealso was processed for paraffin embedding (for immunohistochemisty (IHC)and TUNEL assay). Total RNA was used for Affymetrix microarray with theU133 Plus 2.0 human chip. Differential transcription of genes ofinterest was confirmed by RT-PCR analysis. The TUNEL assay and IHC forKi67 and phosphorylated histone 3 (phospho H3) were applied to paraffinembedded tissue sections, and the percentage of positive stained cellswas noted to assess apoptosis and proliferation. RT-PCR results andproliferation assays were analyzed using two-tailed student t-test;Kruskal-Wallis test was used to assess TUNEL assay results; P<0.05 wasconsidered significant.

Results:

Fibroids exposed to ulipristal had increased measures of apoptosis anddecreased measures of proliferation, compared to PL. Genomic analysisbased on a 2 fold change cut-off and P<0.02 identified 314 genesexpressed differentially between ulipristal and PL. Eight genes ofinterest were chosen because of their potential roles in proliferationor apoptosis and the presence of a progesterone response element in thepromoter. RT-PCR validated the differential expression of Clusterin(Clu), Fas apoptotic inhibitory molecule 2 (FAIM2), Norrie diseaseprotein (NDP), wingless-type MMTV integration site family, member 5A(Wnt5A), B-cell leukemia/lymphoma 2 (Bcl2), sterile-alpha motif andleucine zipper containing kinase AZK (ZAK), proteolipid protein 1 (PLP1)(see the table below).

Fold change of RT-PCR gene product in ulipristal treated compared toplacebo

Gene name Fold change P value Clu −2.1 0.019 FAIM −1.8 0.017 NDP −5.60.001 Wnt5A −2.4 0.008 Bcl2 −1.5 0.224 ZAK 1.5 0.014 PLP1 9.2 0.006

Conclusion:

Fibroid shrinkage associated with ulipristal treatment is accompanied byincreased apoptosis and decreased proliferation and transcriptionalchanges that potentially underlie these observations.

Example 3 Treatment of Benin Metastatic Leiomyoma

A woman with known benign metastatic leiomyoma status post abdominalsurgery that confirmed multiple nodules was treated with ulipristal(daily oral dose of 10-20 mg), in a compassionate protocol. Thetreatment led to resolution of a right pleural effusion, decrease in aliver nodule and some decrease in two uterine fibroids. Moreimportantly, her pulmonary function tests improved from 50% of predictedto 103% of predicted after 3 months of treatment. She felt better.

REFERENCES

-   Attardi et al, Journal of Steroid Biochemistry & Molecular Biology,    2004, 88: 277-288-   Blithe D L, Nieman L K, Blye R P, Stratton P, Passaro M. Steroids.    2003; 68(10-13):1013-7.-   Cramer S F, Patel A. The frequency of uterine leiomyomas. Am J Clin    Pathol. 1990; 94(4):435-8.-   Farquhar C M, Steiner C A. Hysterectomy rates in the United States    1990-1997. Obstet Gynecol. 2002; 99(2):229-34.-   Murphy A A, Morales A J, Kettel L M, Yen S S. Regression of uterine    leiomyomata to the antiprogesterone RU486: dose-response effect.    Fertil Steril. 1995; 64(1):187-90.-   Langer R. New Methods of Drug Delivery. Science 1990; 249:1527-33.-   Somigliana E, Vercellini P, Daguati R, Pasin R, De Giorgi O,    Crosignani P G. Fibroids and female reproduction: a critical    analysis of the evidence. Hum Reprod Update. 2007; 13(5):465-76.-   Zeng C, Gu M, Huang H. [A clinical control study on the treatment of    uterine leiomyoma with gonadotrophin releasing hormone agonist or    mifepristone]. Zhonghua Fu Chan Ke Za Zhi. 1998; 33(8):490-2.

What is claimed:
 1. A method for treating a symptom of uterine fibroidsin a patient, wherein the symptom is selected from the group consistingof uterine bleeding, anemia, pelvic pressure, and pelvic pain, themethod comprising the step of administering to the patient a daily oraldosage of about 5 mg to 20 mg of17α-acetoxy-11β-[4-N,N-dimethylamino-phenyl]-19-norpregna-4,9-diene-3,20-dione(ulipristal acetate).
 2. The method of claim 1, which is for reducing orstopping uterine bleedings as a symptom of uterine fibroids.
 3. Themethod of claim 1, which is for treating anaemia in a patient sufferingfrom uterine fibroids.
 4. The method of claim 1, wherein ulipristalacetate is administered during a period of at least one month.
 5. Themethod of claim 1, wherein ulipristal acetate is administered during aperiod of about 2 to about 4 months.
 6. The method of claim 1, whereinulipristal acetate is administered during about 3 months.
 7. The methodof claim 4, which is repeated once a year.
 8. The method of claim 1,wherein the patient is administered with an oral tablet comprisingulipristal acetate.
 9. The method of claim 1, wherein the patient isadministered with a daily dosage of 10 mg or 5 mg of ulipristal.
 10. Themethod of claim 1, wherein uterine bleeding is reduced or stopped. 11.The method of claim 10, wherein amenorrhea is induced.
 12. The method ofclaim 10, wherein the haematocrit status of the patient is improved. 13.The method of claim 10, wherein the bleeding is reduced or stopped afterthe administration of ulipristal acetate over one menstrual cycle. 14.The method of claim 1, wherein the patient is a pre-menopausal woman.15. The method of claim 1, wherein ulipristal acetate further acts as acontraceptive.
 16. The method of claim 1, wherein the administration ofulipristal acetate is preoperative.
 17. The method of claim 1, whichmethod is further for reducing the size of uterine fibroid in saidpatient.